2-Oxo-1-sulfonyl pyrazolo(1,5-a) pyrimidine-6-carboxylic acid esters

ABSTRACT

Cardiovascular activity is exhibited by compounds having the formula ##STR1## or a pharmaceutically acceptable salt thereof wherein R 1  is alkyl, cycloalkyl, aryl, --(CH 2 ) n  --Y 1 , or halo substituted alkyl; 
     R 2  is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, --(CH 2 ) n  --Y 1 , or halo substituted alkyl; 
     R 3  is hydrogen, alkyl, cycloalkyl, aryl, --(CH 2 ) n  --Y 2 , --(CH 2 ) p  --Y 3 , or halo substituted alkyl; 
     R 4  is aryl; 
     Y 1  is cycloalkyl, aryl, hydroxyl, alkoxy, aryl--(CH 2 ) m  --O--, mercapto, alkylthio, aryl--(CH 2 ) m  --S--, amino substituted amino, carbamoyl, ##STR2## Y 2  is cycloalkyl, aryl, carbamoyl, ##STR3## Y 3  is hydroxyl, alkoxy, aryl--(CH 2 ) m  --O--, mercapto, alkylthio, aryl--(CH 2 )) m  --S--, ##STR4##  amino or substituted amino; m is 0 or an integer of 1 to 6; 
     n is an integer of 1 to 6; and 
     p is an integer of 2 to 6.

BRIEF DESCRIPTION OF THE INVENTION

Compounds having the formula ##STR5## and pharmaceutically acceptablesalts thereof, are cardivascular agents. In formula I, and throughtoutthe specification, the symbols are as defined below.

R₁ is alkyl, cycloalkyl, aryl, --(CH₂)_(n) --Y₁, or halo substitutedalkyl;

R₂ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, --(CH₂)_(n)--Y₁, or halo substituted alkyl;

R₃ is hydrogen, alkyl, cycloalkyl, aryl, --(CH₂)_(n) --Y₂, --(CH₂)_(p)--Y₃, or halo substituted alkyl;

R₄ is aryl;

Y₁ is cycloalkyl, aryl, hydroxyl, alkoxy, aryl--(CH₂)_(m) --O--,mercapto, alkylthio, aryl--(CH₂)_(m) --S--, amino, substituted amino,carbamoyl, ##STR6## Y₂ is cycloalkyl, aryl, carbamoyl, ##STR7## Y₃ ishydroxyl, alkoxy, aryl--(CH₂)_(m) --O--, mercapto, alkylthio,aryl--(CH₂)_(m) --S--, ##STR8## amino or substituted amino, m is 0 or aninteger of 1 to 6;

n is an integer of 1 to 6; and

p is an integer of 2 to 6.

Listed below are definitions of various terms used to describe thecompounds of this invention. These definitions apply to the terms asthey are used throughout the specification (unless they are otherwiselimited in specific instances) either individually or as part of alarger group.

The terms "alkyl" and "alkoxy" refer to both straight and branched chaingroups. Those groups having 1 to 8 carbon atoms are preferred.

The term "halo substituted alkyl" refers to alkyl groups (as describedabove) in which one or more hydrogens have been replaced by chloro,bromo or fluoro groups. Exemplary groups are trifluoromethyl, which ispreferred, pentafluoroethyl, 2,2,2-trichloroethyl, chloromethyl,bromomethyl, etc.

The term "aryl" refers to phenyl and substituted phenyl. Exemplarysubstituted phenyl groups are phenyl groups substituted with one, two orthree alkyl, alkoxy, alkylthio, halo, nitro cyano, trifluoromethyl, ordifluoromethoxy groups.

The terms "alkenyl" and "alkynyl" refer to both straight and branchedchain groups. Those groups having 2 to 8 carbon atoms are preferred.

The term "cycloalkyl" refers to those groups having 3, 4, 5, 6 or 7carbon atoms.

The term "halo" refers to chloro, bromo, fluoro and iodo.

The term "substituted amino" refers to a group of the formula --NZ₁ Z₂wherein Z₁ is hydrogen, alkyl, or aryl--(CH₂)_(m) -- and Z₂ is alkyl oraryl--(CH₂)_(m) --or Z₁ and Z₂ taken together with the nitrogen atom towhich they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl,4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl,4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, or1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl substituted with alkyl,alkoxy, alkylthio, halo, trifluoromethyl or hydroxy.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula I, and the pharmaceutically acceptable saltsthereof, are cardiovascular agents. They act as calcium entry blockingvasodilators and are especially useful as hypotensive agents. Thus, bythe administration of a composition containing one (or a combination) ofthe compounds of this invention, the blood pressure of a hypertensivemammalian (e.g., human) host is reduced. A single dose, or two to fourdivided daily doses, provided on a basis of about 0.1 to 100 milligramsper kilogram of body weight per day, preferably from about 1 to about 50milligrams per kilogram per day, is appropriate to reduce bloodpressure. The substance is preferably administered orally, butparenteral routes such as the subcutaneous, intramuscular or intravenousroutes can also be employed.

As a result of the calcium entry blocking activity of the compounds offormula I, and the pharmaceutically acceptable salts thereof, it isbelieved that such compounds in addition to being hypotensive agents mayalso be useful as anti-arrhythmic agents, anti-anginal agents,anti-fibrillatory agents, anti-asthmatic agents, anti-ischemic agentsand in limiting myocardial infarction.

The compounds of this invention can also be formulated in combinationwith a diuretic, or a beta-adrenergic agent, or angiotensin convertingenzyme inhibitor. Suitable diuretics include the thiazide diuretics suchas hydrochlorothiazide and bendroflumethiazide, suitable beta-adrenergicagents include nadolol, and suitable angiotensin converting enzymeinhibitors include captopril.

The compounds of formula I can be formulated for use in the reduction ofblood pressure in compositions such as tablets, capsules or elixirs fororal administration, or in sterile solutions or suspensions forparenteral administration. About 10 to 500 milligrams of a compound offormula I is compounded with physiologically acceptable vehicle,carrier, excipient, binder, preservative, stabilizer, flavor, etc., in aunit dosage form as called for by accepted pharmaceutical practice. Theamount of active substance in these compositions or preparations is suchthat a suitable dosage in the range indicated is obtained.

To prepare the compounds of formula I, a compound of the formula##STR9## that is, 3-amino-5-pyrazolone, is reacted with a keto esterhaving the formula ##STR10## to provide a compound of the formula##STR11## The reaction is preferably heated in the presence of anorganic solvent, such as dimethylformamide.

Compound IV in solvents, such as dicishloromethane and pyridine, istreated with a compound of the formula

    R.sub.1 O.sub.2 S--Cl                                      V

to provide the compounds of formula I.

The compounds of formula I that contain a basic or acid group form acidaddition and basic salts with a variety of inorganic and organic acidsand bases. The pharmaceutically acceptable salts are preferred, althoughother salts may also be useful in isolating or purifying the product.Such pharmaceutically acceptable acid addition salts include thoseformed with hydrochloric acid, methanesulfonic acid, toluenesulfonicacid, sulfuric acid, acetic acid, maleic acid, etc. Pharmaceuticallyacceptable basic salts include alkali metal salts (e.g. sodium,potassium and lithium) and alkaline earth metal salts (e.g. calcium andmagnesium). The salts can be obtained by reacting the product with anequivalent amount of the acid in a medium in which the saltprecipitates.

Preferred compounds of this invention are those wherein:

R₁ is aryl, R₂ is alkyl (especially methyl), R₃ is alkyl and R₄ issubstituted phenyl (especially 3-nitrophenyl).

The following example are specific embodiments of this invention.

Example 11,2,4,7-Tetrahydro-5-methyl-7-(3-nitro-phenyl)-2-oxo-1-(phenylsulfonyl)pyrazolo-[1,5-a]pyrimidine-6-carboxylicacid, 1-methylethyl ester A.1,2,4,7-Tetrahydro-5-methyl-7-(3-nitro-phenyl)-2-oxopyrazolo[1,5,-a]pyrimidine-6carboxylicacid, 1-methylethyl ester

A mixture of 3-amino-5-pyrazolone (3.57 g, 36.1 mmole) and2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, 1-methylethyl ester (10g, 36.1 mmole) in dry dimethylformamide (30 ml) was heated at 70° C.under argon for 24 hours. The reaction mixture was allowed to cool toroom temperature and then diluted with ether. The resultant precipitatewas filtered off and recrystallized from isopropanol to provide 4.23 gof the title A compound in crystalline form, m.p. 254°-256° C.

Analysis calc'd for C₁₇ H₁₈ N₄ O₅ : C, 56.98; H, 5.06; N, 15.63;

Found: C, 57.18; H, 5.10; N, 15.70.

B.1,2,4,7-Tetrahydro-5-methyl-7-(3-nitro-phenyl)-2-oxo-1-(phenylsulfonyl)pyrazolo-[1,5-a]pyrimidine-6-carboxylicacid, 1-methylethyl ester

The suspension of the title A compound (1.07 g, 3.0 mmol) indichloromethane (10 mL) and pyridine (2 mL) was treated at 0° C. underargon with benzenesulfonyl chloride (0.4 mL, 3.0 mmol). After theaddition was finished, the cooling bath was removed and the reaction wasallowed to stir at room temperature for 3 hours. The resulting solutionwas diluted with dichloromethane and was washed with 1N hydrochloricacid, water and brine. After drying over anhydrous magnesium sulfate,the solvent was removed and the residue was crystallized fromether-hexanes to yield 1.06 g of the title compound as a light yellowsolid, m.p. 187°-188° C.

Analysis calc'd for C₂₃ H₂₂ N₄ O₇ S: C, 55.41; H, 4.45; N, 11.23; S,6.43;

Found: C, 55.22; H, 4.38; N, 10.83; S, 6.62.

EXAMPLES 2-17

Using the procedures outlined above, the following additional compoundsof formula I within the scope of the present invention can be made.

    __________________________________________________________________________     ##STR12##                                                                    Ex. No.                                                                            R.sub.1           R.sub.2       R.sub.3        R.sub.4                   __________________________________________________________________________    2    CH.sub.3          CH.sub.3      CH.sub.2 CH.sub.3                                                                             ##STR13##                3    CH.sub.2 CH.sub.3 CH.sub.3      CH.sub.2 CH.sub.3                                                                             ##STR14##                      ##STR15##                                                                                       ##STR16##    CH.sub.3                                                                                      ##STR17##                5    CH.sub.3 CH.sub.2 CH.sub.2                                                                      CH.sub.2 CH.sub.3                                                                            ##STR18##                                                                                    ##STR19##                6    ClCH.sub.2 CH.sub.3 CH.sub.2                                                                    CH.sub.3                                                                                     ##STR20##                                                                                    ##STR21##                7    CH.sub.3 CH.sub.2 CH.sub.3                                                                                     ##STR22##                                                                                    ##STR23##                8    CH.sub.3                                                                                         ##STR24##                                                                                   ##STR25##                                                                                    ##STR26##                9                                                                                   ##STR27##        CH.sub.3      CH.sub.2 CH.sub.2 OCH.sub.3                                                                   ##STR28##                10                                                                                  ##STR29##        CH.sub.3                                                                                     ##STR30##                                                                                    ##STR31##                11                                                                                  ##STR32##        CH.sub.3      CH.sub. 2 CH.sub.3                                                                            ##STR33##                12   CH.sub.3 CH.sub.2                                                                                ##STR34##    CH.sub.2 CH.sub.3                                                                             ##STR35##                13                                                                                  ##STR36##        CH.sub.3                                                                                     ##STR37##                                                                                    ##STR38##                14                                                                                  ##STR39##        CH.sub.3      CH.sub.2 CH.sub.3                                                                             ##STR40##                15   CH.sub.3                                                                                         ##STR41##                                                                                   ##STR42##                                                                                    ##STR43##                16                                                                                  ##STR44##        CH.sub.3                                                                                     ##STR45##                                                                                    ##STR46##                17   CH.sub.3 CH.sub. 2                                                                              CH.sub.2 CH.sub.2 OCH.sub.3                                                                 CH.sub.2 CH.sub.3                                                                             ##STR47##                __________________________________________________________________________

What is claimed is:
 1. A compound having the formula

    __________________________________________________________________________     ##STR48##                                                                    Ex. No.                                                                            R.sub.1           R.sub.2       R.sub.3        R.sub.4                   __________________________________________________________________________    2    CH.sub.3          CH.sub.3      CH.sub.2 CH.sub.3                                                                             ##STR49##                3    CH.sub.2 CH.sub.3 CH.sub.3      CH.sub.2 CH.sub.3                                                                             ##STR50##                      ##STR51##                                                                                       ##STR52##    CH.sub.3                                                                                      ##STR53##                5    CH.sub.3 CH.sub.2 CH.sub.2                                                                      CH.sub.2 CH.sub.3                                                                            ##STR54##                                                                                    ##STR55##                6    ClCH.sub.2 CH.sub.3 CH.sub.2                                                                    CH.sub.3                                                                                     ##STR56##                                                                                    ##STR57##                7    CH.sub.3 CH.sub.2 CH.sub.3                                                                                     ##STR58##                                                                                    ##STR59##                8    CH.sub.3                                                                                         ##STR60##                                                                                   ##STR61##                                                                                    ##STR62##                9                                                                                   ##STR63##        CH.sub.3      CH.sub.2 CH.sub.2 OCH.sub.3                                                                   ##STR64##                10                                                                                  ##STR65##        CH.sub.3                                                                                     ##STR66##                                                                                    ##STR67##                11                                                                                  ##STR68##        CH.sub.3      CH.sub. 2 CH.sub.3                                                                            ##STR69##                12   CH.sub.3 CH.sub.2                                                                                ##STR70##    CH.sub.2 CH.sub.3                                                                             ##STR71##                13                                                                                  ##STR72##        CH.sub.3                                                                                     ##STR73##                                                                                    ##STR74##                14                                                                                  ##STR75##        CH.sub.3      CH.sub.2 CH.sub.3                                                                             ##STR76##                15   CH.sub.3                                                                                         ##STR77##                                                                                   ##STR78##                                                                                    ##STR79##                16                                                                                  ##STR80##        CH.sub.3                                                                                     ##STR81##                                                                                    ##STR82##                17   CH.sub.3 CH.sub. 2                                                                              CH.sub.2 CH.sub.2 OCH.sub.3                                                                 CH.sub.2 CH.sub.3                                                                             ##STR83##                __________________________________________________________________________

or a pharmaceutically acceptable salt thereof wherein R_(l) is alkyl,cycloalkyl, aryl, --(CH₂)_(n) --Y₁, or halo substituted alkyl; R₂ ishydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, --(CH₂)_(n) --Y₁,or halo substituted alkyl; R₃ is hydrogen, alkyl, cycloalkyl, aryl,--(CH₂)_(n) --Y₂, --(CH₂)_(p) --Y₃, or halo substituted alkyl; R₄ isaryl; Y₁ is cycloalkyl, aryl, hydroxyl, alkoxy, aryl-(CH₂)_(m) --O--,mercapto, alkylthio, aryl--(CH₂)_(m) --S--, amino, substituted amino,carbamoyl, ##STR84## Y₂ is cycloalkyl, aryl, carbamoyl, ##STR85## Y₃ ishydroxyl, alkoxy, aryl--(CH₂)_(m) --O--, mercapto, alkylthioaryl--(CH₂)_(m) --S--, ##STR86## amino or substituted amino; m is 0 oran integer of 1 to 6; n is an integer of 1 to 6; and p is an integer of2 to 6;wherein the terms "alkyl" and "alkoxy" refer to both straight andbranched chain groups having 1 to 8 carbon atoms; the term "halosubstituted alkyl" refers to alkyl groups in which one or more hydrogenshave been replaced by chloro, bromo or fluoro groups; the term "aryl"refers to phenyl and substituted phenyl wherein the substituents are 1,2or 3 groups independently selected from alkyl, alkoxy, allkylthio, halo,nitro cyano, trifluoromethyl, and difluoromethoxy; the terms "alkenyl"and "alkynyl" refer to both straight and branched chain groups having 2to 8 carbon atoms; the term "cycloalkyl" refers to those groups having3, 4, 5, 6 or 7 carbon atoms; the term "halo" refers to chloro, bromo,fluoro and iodo; the term "substituted amino" refers to a group of theformula --NZ₁ Z₂ wherein Z₁ is hydrogen, alkyl, or aryl--(CH₂)_(m) --andZ₂ is alkyl or aryl--(CH₂)_(m) -- or Z₁ and Z₂ taken together with thenitrogen atom to which they are attached are 1-pyrrolidinyl,1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl,1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl,4-diarylalkyl-1-piperazinyl, or 1-pyrrolidinyl, 1-piperidinyl, or1-azepinyl substituted with alkyl, alkoxy, alkylthio, halo,trifluoromethyl or hydroxy.
 2. A compound in accordance with claim 1whereinR₁ is aryl; R₂ is alkyl; R₃ is alkyl; and, R₄ is substitutedphenyl.
 3. A compound in accordance with claim 1 whereinR₁ is phenyl; R₂is methyl; R₃ is isopropyl; and, R₄ is 3-nitrophenyl.
 4. A compound inaccordance with claim 1 having the name1,2,4,7-tetrahydro-5-methyl-7-(3-nitrophenyl)-2-oxo-1-(phenylsulfonyl)pyrazolo-[1,5-a]pyrimidine-6-carboxylic acid, 1-methylethyl ester.
 5. A method forreducing the blood pressure of a mammalian host in need thereof whichcomprises administering to said host an effective amount of a compoundhaving the formula ##STR87## or a pharmaceutically acceptable saltthereof wherein R₁ is alkyl, cycloalkyl, aryl, --(CH₂)_(n) --Y, or halosubstituted alkyl;R₂ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,aryl, --(CH₂)_(n) --Y₁ , or halo substituted alkyl; R₃ is hydrogen,alkyl, cycloalkyl, aryl, --(CH₂)_(n) --Y₂, --(CH₂)_(p) --Y₃, or halosubstituted alkyl; R₄ is aryl; Y₁ is cycloalkyl, aryl, hydroxyl, alkoxy,aryl--(CH₂)_(m) --O--, mercapto, alkylthio, aryl--(CH₂)_(m) --S--,amino, substituted amino, carbamoyl, ##STR88## Y₂ is cycloalkyl, aryl,carbamoyl, ##STR89## Y₃ is hydroxyl, alkoxy, aryl--(CH₂)_(m) --O--,mercapto, alkylthio, aryl--(CH₂)_(m) --S--, ##STR90## m is 0 or aninteger of 1 to 6; n is an integer of 1 to 6; and p is an integer of 2to 6.